The present invention relates to molecular biology in general, with emphasis on proteins affecting the development of metabolic syndrome and related diseases, for example and without limitation, mild cognitive impairment and Alzheimer's Disease.
Metabolic syndrome often refers to a combination of medical disorders that affect a large number of people in a clustered fashion. Metabolic syndrome is generally characterized by a group of metabolic risk factors in one person, including abdominal obesity, atherogenic dyslipidemia (blood fat disorders—high triglycerides, low HDL cholesterol and high LDL cholesterol—that foster plaque buildups in artery walls), elevated blood pressure, insulin resistance, or glucose intolerance, prothrondotic state, and proinflammatory state. Metabolic syndrome is a precursor to many diseases including, but not limited to: mild cognitive impairment, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Sclerosis, corticobasal degeneration, progressive supranuclear palsy, Pick's Disease, and Niemann-Pick's Disease. Oftentimes, the term metabolic syndrome is used to describe the early stages of the diseases listed above and other related diseases.
One of the diseases related to metabolic syndrome, Alzheimer's Disease, affects approximately 4.5 million individuals in the United States, with a projected rise to 14 million individuals by the year 2050. Protein aggregates composed of tau protein and extra cellular plaques of amyloid beta (Aβ) are characteristic pathological features of Alzheimer's Disease affecting the brain and causing behavior changes such as anxiety and loss of synaptic function.
Various risk factors exist and enhance the probability of an individual to develop Alzheimer's Disease. One major factor is age, while another major factor is Type II diabetes. Overeating and obesity are common causes of insulin resistance leading to Type II diabetes. In fact, simply being overweight (i.e., having a body mass index of greater than 25) raises the risk of an individual developing Type II diabetes. Conversely, most individuals with Type II diabetes develop mild cognitive impairment and ultimately Alzheimer's disease. In the past 50 years, there has been a dramatic shift in the rise of Alzheimer's Disease cases. High fat diets have been shown to induce insulin resistance, but less is known about the effects of sugar intake. Alzheimer's Disease may be Type III diabetes.
The p62 protein operates in both receptor mediated activation of kinase cascades and in ubiquitin signaling. P62 serves as a polyubiquitin chain binding protein and is a scaffold for the atypical protein kinase C (aPKC). P62 also serves to traffic proteins to a structure known as an aggresome which is a region of a cell where proteins are sorted and routed to other cellular compartments. The sequestration of aggregates in the aggresome protects cells that are dependent upon the ability of the p62 protein to bind polyubiquinated proteins through its C terminal ubiquitin associated domain. Conversely, the N-terminus of the p62 protein interacts with a proteasome, which is a large protein complex that degrades proteins tagged for elimination, particularly those tagged with ubiquitin. Accordingly, p62 plays a role in protein degradation by shuttling proteins from a sorting compartment, the aggresome, to the degradation department, the proteasome. Alternatively, p62 may also transport polyubiquitinated proteins for degradation by the autophagosome. Protein p62 also interacts with members of the Trk transmembrane protein family, and an absence in p62 impairs Trk internalization and signaling.
The TrkB family of transmembrane proteins serves as receptors for neurotrophic factors. Specific mutations in TrkB have been linked to regulation of food intake, body weight control, obesity and insulin resistance. Mutations in the TrkB transmembrane protein, as well as brain-derived neurotrophic factor, have been linked to Alzheimer's Disease. Geetha and Wooten have demonstrated that TrkB exerts its physiological effects through association with signal scaffolds, such as the p62 protein, J. Biol. Chem. 278 (7): 4730-4739.
It was surprisingly found that the p62 protein has a profound effect on the pathways that cause hyperphosphorylation and polyubiquination of tau proteins, and deposits of APP/amyloid beta. The hyperphosphorylation of tau and its accumulation is coincident with development of insulin resistance. Thus, disturbances in p62 protein expression lead to metabolic syndrome, Alzheimer's Disease and may be a contributing factor to development of other neurodegenerative diseases.
By detecting the absence of p62 protein, a method for screening a mammal for metabolic syndrome or related diseases is established. Since the p62 protein is intricately involved in the accumulation of tau protein and amyloid beta protein, and is also involved in creating insulin resistance in mammals, p62 is a metabolic marker for cognitive decline, and the detection of the presence/absence/concentration of p62 in mammalian tissues provides a mechanism for the early detection of neurological diseases, such as Alzheimer's Disease and various other related neurological diseases. The detection of the absence of p62 protein can be accomplished by supplying a tissue sample, extracting proteins from the tissue sample, and analyzing the extracted proteins to determine whether p62 is present or absent. It is contemplated that this type of detection will diagnose a predisposition for metabolic syndrome, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, corticobasal degeneration, progressive supranuclear palsy, Pick's Disease, and/or Niemann-Pick's Disease.
A method for screening a mammal for metabolic syndromes comprising the steps of detecting the level of p62 protein in a metabolic pathway, and determining whether the level of p62 protein in the metabolic pathway is below a threshold level is also contemplated. This method further includes obtaining a tissue sample, extracting proteins from the tissue sample and analyzing the extracted proteins to determine the concentration of the p62 protein within the sample. Alternatively, if tissue sample is limiting, p62 levels can be detected using Quantitative PCR (QPCR) techniques.
A pharmaceutical composition for therapeutic supplementation of a metabolic pathway is also contemplated. The composition comprises p62 protein or an amide, ester or salt thereof and a pharmaceutically effective carrier. Such pharmaceutical composition would have an inhibitory action on phosphorylation of tau protein and extracellular plaques of amyloid beta and would also operate to lower blood insulin levels and may alter feeding behavior.